Prior research has shown that neurons within the spinal cord are sensitive to response-outcome (instrumental) relations. Learning in the isolated spinal cord has been studied by cutting communication with the brain using a thoracic transection. Transected rats given shock to one hind leg whenever the leg is extended learn to maintain the leg in a flexed position, thereby minimizing net shock exposure. Rats given shock independent of leg position (uncontrollable shock) do not learn and exhibit a learning deficit when later tested with controllable shock. Evidence suggests that uncontrollable stimulation impairs learning because it induces a form of central sensitization that saturates NMDA receptor mediated plasticity. Uncontrollable stimulation also impairs recovery after a contusion injury. Just 6 min of stimulation 24 hrs after injury leads to poor sensory/motor recovery and this effect is evident 6 weeks later. Uncontrollable stimulation also increases the incidence of renal failure and signs of neuropathic pain. Our working hypothesis is that unregulated nociceptive transmission (pain signals) engages cellular mechanisms that impair recovery after spinal injury. Our long-term objectives are to identify: the circumstances that cause this effect, the neurobiological mechanisms involved, and procedures that can be used to block the adverse effect of uncontrollable nociceptive stimulation. Three aims are proposed that will detail the stimulus conditions that impact recovery, the relative role of brain systems, and the relation to central sensitization. The experiments build on a decade of research detailing the conditions, and neurobiological mechanisms, that impact function in the isolated spinal cord. Aim 1 examines the stimulus conditions that affect recovery. It is recognized that a moderate contusion spares some sensory fibers that allow pain transmission to supraspinal structures. It is not known whether, and how, brain systems contribute to the long-term effects of stimulation on recovery. If brain systems are involved, less intense, and more widely spaced, stimulation should impact recovery. Aim 2 will clarify the role of brain systems using physiological and pharmacological manipulations that impact spared fibers. We also examine whether stimulation affects recovery in the absence of input at, or below, the site of injury. Aim 3 will evaluate whether the induction of central sensitization (through peripheral inflammation) impairs recovery and whether pharmacological manipulations that prevent central sensitization have a protective effect. The loss of tissue after neural injury reflects the net effect of both the acute injury and secondary processes that extend from hours to days after injury. By identifying factors that influence these secondary processes, treatments can be developed to reduce their harmful effects. Treatments now used to control pain in other situations (e.g., an epidural) could benefit recovery. The present grant will evaluate this possibility. [unreadable] [unreadable] [unreadable]